Dihydroorotate Dehydrogenase Inhibitors for Treating Acute Myelogenous Leukemia (AML)

Important Compound Classes

Title

Dihydroorotate Dehydrogenase Inhibitors

Patent Publication Number

WO 2020/212897 A1

Publication Date

October 22, 2020

Priority Application

US 62/835,113

Priority Date

April 17, 2019

Inventors

Kuduk, S.; Zhang, Z.; Deratt, L.; Wang, A.

Assignee Company

Janssen Biotech, Inc., USA

Disease Area

Acute myelogenous leukemia (AML)

Biological Target

Dihydroorotate dehydrogenase

Summary

Acute myelogenous leukemia (AML) is a clonal disease of the blood and bone marrow resulting from mutations that occur in normal hematopoietic stem cells. AML is a heterogeneous disease in that it presents with a range of cytogenetic, morphological, and immunophenotypic features and is characterized by a accumulation of clonal, abnormal myeloid progenitor cells, known as myeloblasts. These cells demonstrate disruption of normal myeloid differentiation and excessive proliferation, resulting in the decreased formation of hematopoietic cells.

Dihydroortate dehydrogenase (DHODH) is a flavin mononucleotide (FMN) flavoprotein located in the inner mitochondrial membrane that catalyzes the oxidation of dihydroortate to orotate, the fourth step in the de novo pyrimidine biosynthesis pathway. Inhibition of DHODH decreased pyrimidine synthesis, important precursors for nucleotide synthesis, but also glycoprotein and phospholipid biosynthesis. DHODH inhibition drives AML differentiation in vitro and results in dose dependent antileukemic effects, decreased leukemic stem cells, and prolonged survival in vivo. Small molecule DHODH inhibitors mediate antiproliferative activity against AML cells with concomitant cell cycle arrest and induction of apoptosis.

The present application describes a series of novel DHODH inhibitors and are useful for treatment of cancer, autoimmune and inflammatory diseases, particularly for the treatment of acute myelogenous leukemia (AML). Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = CH or N;

Y = CH or N;

R₁ = C_1–6alkyl; C_1–6alkyl substituted with OH, or OCH₃; C_2–6alkenyl; C_1–6haloalkyl; C_1–6haloalkyl substituted with OH, or OCH₃; C_2–6haloalkenyl; N(CH₃)₂; C_3–6cycloalkyl; C_3–6cycloalkyl substituted with C_1–6alkyl; and phenyl;

R₂ = ; wherein

R_a = C_1–6alkyl, C_1–6haloalkyl, and C_3–6cycloalkyl;

R_b = C_1–6alkyl or C_1–6alkyl substituted with a member selected from the group consisting of OH, halo, CN, OC_1–6alkyl, OC_1–6haloalkyl, and OC_3–6cycloalkyl;

R₃ = H, halo, CH₃, and OCH₃;

R₄ = C_1–6alkyl; C_1–6alkyl substituted with one or more OCH₃; C_3–6cycloalkyl; C_3–6cycloalkyl substituted with CH₃ or OCH₃; CH₂–C_3–6cycloalkyl; and ; ; , , , , , , , and ; and , , and ; wherein

R_c = H, halo, C_1–6alkyl or C_1–6alkyl substituted with a member selected from the group consisting of OH, OCH₃, SCH₃, and OCF₃;

R_d = H, halo, C_1–6alkyl or C_1–6alkyl substituted with a member selected from the group consisting of OH, OCH₃, SCH₃, and OCF₃;

R_g = H, halo, C_1–6alkyl or C_1–6alkyl substituted with a member selected from the group consisting of OH, OCH₃, SCH₃, and OCF₃; and

n = 1 or 2.

Key Structures

Biological Assay

In vitro DHODH enzymatic assay and in vitro MOLM-13 cellular assay were performed. The compounds described in this application were tested for their ability to inhibit MOLM-13 and DHODH. The MOLM-13 IC₅₀ (nM) and DHODH IC₅₀ (nM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for MOLM-13 and DHODH inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 36

Compound claims: 27

Pharmaceutical composition claims: 2

Method of treatment claims: 7

Recent Review Articles

• 1.Boukalova S.; Hubackova S.; Milosevic M.; Ezrova Z.; Neuzil J.; Rohlena J.. Biochim. Biophys. Acta, Mol. Basis Dis. 2020, 1866, 165759.
• 2.Wojcicki A. V.; Kasowski M. M.; Sakamoto K. M.; Lacayo N.. Mol. Genet. Matab. 2020, 130, 230.
• 3.Madak J. T.; Bankhead A. III; Cuthbertson C. R.; Showalter H. D.; Neamati N.. Pharmacol. Ther. 2019, 195, 111.
• 4.Chrisophersen A.; Risnes L. F.; Dahal-Koirala S.; Sollid L. M.. Trends Mol. Med. 2019, 25, 836.

The author declares no competing financial interest.